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Introduction Inhaled mannitol has beneficial effects on lung function, mucociliary clearance, quality of life and sputum properties. This trial examined the efficacy of inhaled mannitol in children with cystic fibrosis (CF). Methods The efficacy of inhaled mannitol in children with CF aged 6–17 years was assessed in a phase 2, randomised, placebo-controlled crossover study. Subjects were randomly assigned to mannitol 400 mg every 12 h or matching placebo for 8 weeks, followed by an 8 week washout and an 8 week period with the alternate treatment. The primary endpoint was the absolute change from baseline in ppFEV1 (percent predicted FEV1). Results A total of 92 subjects were studied, with a mean age of 12 years and mean baseline ppFEV1 of 72.2%. During mannitol treatment ppFEV1 was 3.42% (p = 0.004) higher compared to placebo or a 4.97% (p = 0.005) relative difference; relative change from baseline FEF25-75 was 10.52% (p = 0.013). During mannitol treatment, acute post-treatment sputum weight was higher (p = 0.012). In pre-specified subgroups (rhDNase use, age, and disease severity), the treatment differences consistently favoured mannitol. The most common AEs were cough and pulmonary exacerbations. Pulmonary exacerbation AEs were approximately 30% lower in the mannitol group. Conclusions In children with CF, inhaled mannitol was associated with significant improvements in lung function and sputum weight, irrespective of rhDNase use, age or disease severity. Inhaled mannitol was well tolerated and was associated with a reduced incidence of pulmonary exacerbation AEs. (Clinical Trials.Gov: NCT 01883531) [ABSTRACT FROM AUTHOR]

Background. Systemic steroids and adjunctive anti fungal therapy are the cornerstone in treating allergic bronchopulmonary aspergillosis (ABPA) in the context of CF. Aim. Evaluate the use of inhaled amphotericin B (iAMB) as antifungal agent in this context. Methods. Report of 7 CF patients with recurrent or difficult to treat ABPA and failure to taper systemic corticosteroids treated with AMB deoxycholate (AMB-d) (Fungizone 25mg 3× a week) or AMB lipid complex (ABLC) (Abelcet 50mg twice weekly). Successful therapy was defined as steroid withdrawal without ABPA relapse within 12 months. Results. Therapy was successful in 6 of 7 patients treated with iAMB. In 5/6, lung function improved. The patient with treatment failure has concomitant MAC lung infection. Conclusion. Inhaled AMB may be an alternative to commonly used adjunctive antifungal therapy in the treatment of ABPA. More data are needed on safety and efficacy. [ABSTRACT FROM AUTHOR]

Background: In the management of cystic fibrosis (CF), rhDNase-I inhalation is widely used to facilitate the removal of the highly viscous and elastic mucus (often called sputum) from the lungs. However, an important group of CF patients does not benefit from rhDNase-l treatment. A study was undertaken to elucidate the reason for the failure of rhDNase-I in these patients and to evaluate strategies to overcome this. Methods: The biochemical properties, physical properties, and degradation by rhDNase-I of sputum obtained from clinical responders and non-responders to rhDNase-I were compared, and the ability of magnesium to reactivate rhDNase-I in DNA solutions and in sputum was investigated. The effect of oral magnesium supplements on magnesium levels in the sputum of patients with CF was also examined. Results: Sputum from clinical responders was extensively degraded in vitro on incubation with rhDNase-I, while sputum from clinical non-responders was not degraded: the median decrease in sputum elasticity in the two groups was 32% and 5%, respectively. Sputum from clinical responders contained significantly higher concentrations of magnesium than sputum from non-responders (2.0 mM v 1.3 mM; p=0.020). Sputum that could not be degraded by rhDNase-I became degradable after preincubation with magnesium. The effect of magnesium on rhDNase-I activity was mediated through actin. Oral intake of magnesium enhanced the magnesium concentration in the sputum of CF patients. Conclusion: Increasing the magnesium concentration in sputum by, for example, oral magnesium supplements may be a promising new strategy to overcome the failure of rhDNase-I in patients with CF. [ABSTRACT FROM AUTHOR]

Objectives Treating early PA infection in CF often requires giving inhaled antibiotics to very young patients (pts). In the ALPINE study ( ClinicalTrials.gov NCT01375049 ), pts <6 yrs old were allowed to use a facemask rather than the standard nebulizer mouthpiece. Post-hoc analysis was performed to compare results of AZLI treatment for pts using a facemask vs. mouthpiece. Methods Children age 3 mos to <18 yrs with CF and new onset PA infection (first lifetime PA -positive culture [throat swab, sputum, BAL] or PA -positive after ≥2-yr history of PA -negative cultures) were treated with AZLI 75 mg 3x/day for 28 days via a PARI Investigational eFlow® Nebulizer. Recommended delivery was by SmartMask® Baby for pts 3 mos to <2 yrs, SmartMask Kids for 2 to <6 yrs, and by nebulizer mouthpiece for ≥6 yrs. Masks and mouthpiece were interchangeable to obtain optimal fit. Evaluable pts received a full 28 day AZLI course and no additional anti-PA antibiotics. Use of delivery devices by age group and respective PA eradication failure rates are presented. Results See the table. No specific safety issues were attributable to either mask or mouthpiece use. PA culture positive at day 28, end of treatment, n/N 3 mo to <2 yrs 2 to <6 yrs 6 to <18 yrs Total Masks 4/46 (8.7%)  SmartMask Baby 2/18 0/1 0/0  SmartMask Kid 1/5 1/19 0/3 Mouthpiece 0/0 0/4 6/50 6/54 (11.1%) Conclusion In young children with CF, AZLI treatment administered via eFlow nebulizer with SmartMask for initial PA infection had high eradication success rates and should be considered a valid treatment option. No safety issues were associated with specific mask/mouthpiece type. Supported by Gilead Sciences. [ABSTRACT FROM AUTHOR]

Objectives In the ALPINE study ( ClinicalTrials.gov NCT01375049), AZLI treatment for 28 days in children with CF age 3 months to <18 yrs with new onset PA infection resulted in culture-negativity in 89% of patients (pts) at end of treatment and in 75% of pts at 28 days post-treatment. Post-hoc analyses were performed to determine possible factors associated with failure to eradicate or regrowth of PA post-treatment. Methods Children age 3 mos to <18 yrs with CF and new onset PA infection (first lifetime PA -positive culture [throat swab, sputum, BAL] or PA -positive after ≥2-yr history of PA -negative cultures) were treated with AZLI 75 mg 3x/day for 28 days via PARI Investigational eFlow® Nebulizer. Evaluable pts received a full 28 day AZLI course and no additional anti- PA antibiotics. Baseline (BL) factors were compared for pts with post-treatment cultures PA -positive vs. those who were PA -negative. Results 99 treated pts had culture data available at 28d post-treatment: PA was present in 23; absent in 76. No differences were seen in age, CF genotype, history of prior PA infection, FEV1 % predicted, PA antibody status, or presence of co-infecting pathogens at BL in PA present vs. absent groups. 22/23 pts who failed eradication were >90% treatment compliant. MIC50&90 were unchanged in PA strains isolated post-treatment vs. BL (4, 8 mg/mL respectively). Conclusion No BL factors examined predicted PA culture positivity after a 28-day course of AZLI. Inhaled antibiotic treatment is warranted for all pts with new onset PA infection. Further studies are needed to determine optimal treatment strategies for initial eradication failures. Supported by Gilead Sciences. [ABSTRACT FROM AUTHOR]

• Advancement of the CF therapeutics pipeline remains an important goal. • Availability of CFTR modulators impacts future CF clinical development. • Global strategies are required for successful clinical development. • Partnership from key stakeholders is necessary to align on optimal paths forward. • Input from the CF community is needed to ensure informative yet feasible studies. As CFTR modulator therapy transforms the landscape of cystic fibrosis (CF) care, its lack of uniform access across the globe combined with the shift towards a new standard of care creates unique challenges for the development of future CF therapies. The advancement of a full and promising CF therapeutics pipeline remains a necessary priority to ensure maximal clinical benefits for all people with CF. It is through collaboration across the global CF community that we can optimize the evaluation and approval process of new therapies. To this end, we must identify areas for which harmonization is lacking and for which efficiencies can be gained to promote ethical, feasible, and credible study designs amidst the changing CF care landscape. This article summarizes the counsel from core advisors across multiple international regions and clinical trial networks, developed during a one-day workshop in October 2019. The goal of the workshop was to identify, in consideration of the highly transitional era of CFTR modulator availability, the drug development areas for which global alignment is currently uncertain, and paths forward that will enable advancement of CF therapeutic development. [ABSTRACT FROM AUTHOR]

Abstract: In patients with cystic fibrosis (CF), treatment of new Pseudomonas aeruginosa (Pa) infection postpones the occurrence of chronic infection, but the best eradication regimen is unknown . Aim of the study: Compare 2 Pa eradication regimens in children with new Pa infection. Methods: Children with CF (0–18years) and a new isolation of Pa from sputum, cough swab or BAL were randomized to treatment with tobramycin inhalation solution for 28days (TIS) or inhaled sodiumcolistimethate (2×2millU/day) plus oral ciprofloxacin (30mg/kg/day) for 3months (CC). Airway cultures were taken for 6 consecutive months, then every 3months. The primary outcome was Pa eradication at the end of treatment. Secondary outcome parameters were: time to Pa relapse from end of treatment, total and Pa specific IgG, FEV1, BMI and Pa status at 2year follow-up. Results: 58 patients with new Pa isolation were randomized. Their median age was 9years (IQR 4.7–13.1) and their median FEV1 98% predicted (IQR 87–107). Eighteen treatments concerned the first Pa isolation ‘ever’ (TIS: 8; CC: 10). For the remaining, median time since previous Pa was 19months (IQR 9–41). Eradication at end of treatment was similar for both treatments: 26/29 CC and 23/29 in TOBI treated patients (p=0.47). Median time to recurrence of Pa was 9months (95% CI 0.0–19.0) for CC and 5months (95% CI 1.7–8.3) for TIS (p=0.608). After 1year, the 2 groups did not differ in change in total and Pa specific IgG, FEV1 and BMI. After 2years, 10% of patients had chronic Pa infection. Conclusion: In children with CF and new Pa infection, inhalation of TIS (28days) or CC (3months) resulted in similar eradication success at the end of treatment (80 and 90% respectively) and similar clinical evolution during the first 2years of follow-up. [Copyright &y& Elsevier]